At present, a broad challenge that confronts the field of gene delivery is the development of synthetic materials that permit the delivery of DNA to cells with spatial and temporal control. Materials that provide such control could be useful as tools for basic biological and biomedical research as well as in applications such as tissue engineering and the development of gene-based therapies. Cationic lipids have been investigated widely for gene delivery because they aggregate with DNA to form lipid/DNA complexes (lipoplexes) that transport DNA into cells (Zhang, et al. J Control Release 2004, 100, 165-80; Kabanov, et al. Self-Assembling Complexes for Gene Delivery: From Laboratory to Clinical Trial. John Wiley and Sons: New York, 1998). However, conventional lipoplexes are generally active (and thus able to transfect cells) beginning from the time at which they are first formed. As a result, maintaining spatial and temporal control over the transfection of a subset of cells within a larger population presents a significant challenge. The design of functional lipids that permit the localized activation of lipoplexes that are otherwise inactive (and thus do not transfect cells) would make possible new approaches to the delivery of DNA with both spatial and temporal control (Guo, et al., Accounts of Chemical Research 2003, 36, 335-341; Shum, et al., Adv Drug Deliv Rev 2001, 53, 273-84).
Several past investigations have reported on the design of lipids that respond to local variations in the intracellular environment (e.g., changes in pH, Guo, et al., Accounts of Chemical Research 2003, 36, 335-341; Budker, et al., Nature Biotechnology 1996, 14, 760-764; Reddy, et al., J Control Release 2000, 64, 27-37 reducing potential, Guo, et al., Accounts of Chemical Research 2003, 36, 335-341; Tang, et al., Biochemical and Biophysical Research Communications 1998, 242, 141-145; Huang, et al., Molecular Therapy 2005, 11, 409-417 or the presence of enzymes Guo, et al., Accounts of Chemical Research 2003, 36, 335-341; Meers, Adv Drug Deliv Rev 2001, 53, 265-72; Prata, et al., J Am Chem Soc 2004, 126, 12196-7) that expose latent functionality or ‘activate’ a lipid toward a specific secondary function. The design of these lipids has been driven largely by the need for DNA delivery agents that address specific and important intracellular barriers to transfection (Guo, et al., Accounts of Chemical Research 2003, 36, 335-341). However, because the transformation of these lipids is designed to occur in the intracellular environment, the timing and the location of the ‘activation’ of these lipids is under cellular control. However, these previous approaches do no achieve localized activation of lipids and lipoplexes using externally controlled stimuli.
In a recent communication, Abbott, et al. reported the results of an investigation to determine the ability of a two-tailed ferrocene-containing cationic lipid, bis(11-ferrocenylundecyl)dimethylammonium bromide to interact with DNA and transfect mammalian cells (J Am Chem Soc 2005, 127, 11576-7, incorporated by reference herein in its entirety). The structure of BFDMA is shown in FIG. 1 and has been previously described (Kakizawa, et al., Langmuir 1996, 12, 921-924; Kakizawa, et al., Langmuir 2001, 17, 8044-8048).
Beyond the gene delivery context, several groups have observed that redox-active amphiphiles are capable of achieving active electrochemical control over various surfactant/polymer properties in aqueous systems (e.g., Saji, et al., Journal of the American Chemical Society 1991, 113, 450-456)). Recently, Hays et al. demonstrated that the cationic surfactant 11-(ferrocenylundecyl)trimethylammonium bromide (FTMA, structure shown in FIG. 1), when combined with electrochemical methods, can be used to control interactions between the surfactant and a synthetic polymer in aqueous solution (Hays, et al., Langmuir 2005, 21, 2007-12015, incorporated by reference herein in its entirety). The ability to control the physical properties of polymers in solution would find broad applicability in the manipulation of polymer size, rheological properties, aggregation state, gelation, optical appearance, electrical properties, and phase behavior.
At present, there exists a need for improved materials and methods to achieve active spatial and temporal control over the delivery of nucleic acids to cells in the context of transfection. As well, the technology to control the physical properties of polymers in solution would find broad applicability in industrial applications where, for example, polymer aggregation state or optical appearance are critical parameters.